Tunica interna endothelial cell kinase-2 (TIE2) is largely restricted to expression in endothelial cells of the vasculature, and in a subset of bone marrow derived TIE2 expressing monocytes (TEMs). TIE2 is the receptor for angiopoietin 1 (ANG1), angiopoietin 2 (ANG2), and angiopoietin 4 (ANG4) and this signaling system plays an important role in both angiogenesis (sprouting of new vessels from existing vessels) and vasculogenesis (de novo new vessel formation). TEMs are a subset of circulating monocytes and tissue macrophages that have proangiogenic and provasculogenic activity in tumor models (De Palma M D et al, Cancer Cell 2005; 8:211-226). TIE2 inhibition decreases the ability of TEMs to associate with blood vessels (Mazzieri R, Cancer Cell 2011; 19:512-526) and markedly decreases the proangiogenic activity of this macrophage subset (De Palma M, Clin Cancer Res 2011; 17(16):5226-5232).
Cytotoxic chemotherapy, radiation therapy, and anti-angiogenic treatments damage the tumor-associated vasculature thus leading to a hypoxic tumor environment. The hypoxic tumor environment leads to rebound tumor vascularization by activating an angiogenic switch from the vascular endothelial growth factor (VEGF)/VEGFR2 pathway to the ANG/TIE2 pathway in vascular endothelial cells. The recruitment of pro-vasculogenic TEMs from the bone marrow to these hypoxic tumor sites facilitates this revascularization by the association of TEMs with endothelial cells within the tumor microenvironment. TEMs and TIE2-expressing endothelial cells are thus believed to play an important role in the revascularization of tumors after these treatments, leading to progression due to the growth of residual tumor cells (De Palma M, et al. Trends Immunol 2007; 28:519-524).
TIE2 is also a mediator of osteoclast differentiation, and TIE2 inhibition led to decreased osteolytic bone invasion and decreased tumor growth in the 4T1 mouse breast cancer model (Dales J P, et al. Int J Oncol 2003; 22:391-397). Beyond the physiologic expression of TIE2 on endothelial, monocyte/macrophage, and osteoclast cells of the tumor microenvironment, TIE2 has also been demonstrated to be present on breast cancer cells. Tumor cell expression of TIE2 was associated with an elevated risk of metastatic disease and an independent predictor of prognosis on multivariate analysis (Min Y, et al. Cancer Res 2010; 70:2918-2828).
Significantly, a subset of TIE2-expressing tissue macrophages are located within specialized vascular structures known as tumor microenvironment for metastases (TMEMs). Recent observations have linked TIE2-expressing macrophages within TMEM structures as being essential for extravasation of breast cancer cells into the vascular circulation and subsequent dissemination to distal metastatic sites (Condeelis J, Pollard J W. Cell 2006; 124:263-6; Ginter P S, et al. Cancer Res 2012; 72(24 Suppl):Abstract #P6-02-04). Thus inhibition of TIE2, and of the macrophages within TMEM structures, may lead to a decrease in new metastases.
TIE2-expressing tissue macrophages (TEMs) have recently been demonstrated to play a role in breast cancer immunotolerance. TEMs from breast tumors are able to suppress tumor-specific immune responses. Specifically, suppressive functions of TEMs are similarly driven by TIE2 and VEGFR kinase activity. TEMs isolated from breast cancer tissue can function as antigen-presenting cells that elicit only a weak proliferation of T cells. Blocking TIE2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells with robust antigen-presentation. Immunosuppressive activity of TEMs is also associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE2 and VEGFR kinase activities were required to maintain high CD86 surface expression levels and to convert T cells into immunosuppressive regulatory cells (Ibberson M, et al. Clin Cancer Res 2013; 19:3439-3449).
The polyoma middle-T antigen (PyMT) syngeneic mouse breast cancer model utilizes the mouse mammary tumor virus (MMTV) promoter, a breast specific promoter, to express PyMT in mouse breast tissue. In this model, PyMT breast cancer cells are implanted in the mouse mammary fat pad, and these cancers metastasize and lead to the death of the mouse. Unlike xenograft models, the PyMT model utilizes fully immunocompetent mice. Metastasis in this model is known to be modulated by TIE2 expressing macrophages within TMEM vascular structures. Thus, there is a need for new treatments for diseases associated with TIE2.